The proposed work is an attempt to gain some insight into the mechanisms involved in the development of resistance to penicillin which has become evidenced within the last ten to fifteen years. Four different parameters will be looked into: a) binding of radioactive penicillin to whole cells and subcellular fractions. Preliminary work already performed in this laboratory indicates an inverse relationship between binding of penicillin and sensitivity to the antibiotic; b) evidence from preliminary work done in vitro in this laboratory, and observation of clinical material directly from another, indicate that particularly under the impact of penicillin, cell-wall defective variants, possibly of the L-form type, accumulate. Conceivably such transformation could account for resistance. An in vitro system consisting of gonococci, white blood cells, prostatic fluid and labeled penicillin will be used to follow both colonial morphology and binding and morphological changes of cells; c) based on preliminary observations in this laboratory, a particle has been found on electron microscopic observation of plaque-like areas in confluent cultures of the gonococcus; d) search for enzymes capable of inactivating penicillin, such as beta-lactamase and penicillin acylase.